Inhibition of the left medial prefrontal cortex (mPFC) prolongs the social defeat-induced anxiogenesis in mice: Attenuation by NMDA receptor blockade in the right mPFC.

Chemical inhibition and nitrergic stimulation of the left and right medial prefrontal cortex (L and RmPFC), respectively, provoke anxiety in mice. Moreover, LmPFC inhibition immediately followed by a single social defeat stress (SDS) led to anxiogenesis in mice exposed to the elevated plus maze (EPM) 24 h later. Given that glutamate NMDA (N-methyl-D-aspartate) receptors are densely present in the mPFC, we investigated (i) the time course of LmPFC inhibition + SDS-induced anxiogenesis and (ii) the effects of intra-RmPFC injection of AP-7 (a NMDA receptor antagonist) on this long-lasting anxiety. Male Swiss mice received intra-LmPFC injection of CoCl2 (1 mM) and 10 min later were subjected to a single SDS episode and then (i) exposed to the EPM 2, 5, or 10 days later or (ii) 2 days later, received intra-RmPFC injection of AP-7 (0.05 nmol) and were exposed to the EPM to observe the percentage of open arm entries and time (%OE; %OT) and frequency of closed arm entries (CE). Dorsal but not ventral LmPFC inhibition + SDS reduced open arm exploration 2, 5, and 10 days later relative to that of saline-treated or non-defeated mice. Moreover, this effect is not due to locomotor impairment as assessed using the general activity. Intra-RmPFC AP-7 injection 2 days after LmPFC inhibition + SDS prevented this type of anxiogenesis. These results suggest that the integrity of the LmPFC is important for mice to properly cope with SDS, and that NMDA receptor blockade in the RmPFC facilitates resilience to SDS-induced anxiogenesis in mice.

Amygdaloid involvement in the defensive behavior of mice exposed to the open elevated plus-maze.

Previous studies have shown that the exposure to an open elevated plus maze (oEPM, an EPM with all four open arms) elicits fear/anxiety-related responses in laboratory rodents. However, very little is known about the underlying neural substrates of these defensive behaviors. Accordingly, the present study investigated the effects of chemical inactivation of the amygdala [through local injection of cobalt chloride (CoCl2: a nonspecific synaptic blocker)] on the behavior of oEPM-exposed mice. In a second experiment, the pattern of activation of the basolateral (BLA) and central (CeA) nuclei of the amygdala was assessed through quantification of Fos protein expression in mice subjected to one of several behavioral manipulations. To avoid the confound of acute handling stress, 4 independent groups of mice were habituated daily for 10days to an enclosed EPM (eEPM) and, on day 11 prior to immunohistochemistry, were either taken directly from their home cage (control) or individually exposed for 10min to a new clean holding cage (novelty), an eEPM, or the oEPM. An additional group of mice (maze-naïve) was not subjected to either the habituation or exposure phase but were simply chosen at random from their home cages to undergo an identical immunohistochemistry procedure. Results showed that amygdala inactivation produced an anxiolytic-like profile comprising reductions in time spent in the proximal portions of the open arms and total stretched attend postures (SAP) as well as increases in time spent in the distal portions of the open arms and total head-dipping. Moreover, Fos-positive labeled cells were bilaterally increased in the amygdaloid complex, particularly in the BLA, of oEPM-exposed animals compared to all other groups. These results suggest that the amygdala (in particular, its BLA nucleus) plays a key role in the modulation of defensive behaviors in oEPM-exposed mice.

Role of TRPV1 channels of the dorsal periaqueductal gray in the modulation of nociception and open elevated plus maze-induced antinociception in mice.

Recent findings have identified the presence of transient receptor potential vanilloid-1 (TRPV1) channels within the dorsal portion of the periaqueductal gray (dPAG), suggesting their involvement in the control of pain and environmentally-induced antinociception. Environmentally, antinociception may be achieved through the use of an open elevated plus maze (oEPM, an EPM with 4 open arms), a highly aversive environmental situation. Here, we investigated the role of these TRPV1 channels within the dPAG in the modulation of a tonic pain and in the oEPM-induced antinociception. Male Swiss mice, under the nociceptive effect of 2.5% formalin injected into the right hind paw, received intra-dPAG injections of the TRPV1 agonist (capsaicin: 0, 0.01, 0.1 or 1.0 nmol/0.2 µL; Experiment 1) or antagonist (capsazepine: 0, 10 or 30 nmol/0.2 µL; Experiment 2) or combined injections of capsazepine (30 nmol) and capsaicin (1.0 nmol) (Experiment 3) and the time spent licking the formalin-injected paw was recorded. In Experiment 4, mice received intra-dPAG capsazepine (0 or 30 nmol) and were exposed to the oEPM or to a control situation, an enclosed EPM (eEPM; an EPM with 4 enclosed arms). Results showed that while capsaicin (1 nmol) decreased the time spent licking the formalin-injected paw, capsazepine did not change nociceptive response. Capsazepine (30 nmol) blocked pain inhibition induced by capsaicin and mildly attenuated the oEPM-induced antinociception. Our results revealed an important role of TRPV1 channels within the dPAG in the modulation of pain and in the phenomenon known as fear-induced antinociception in mice.

Anxiogenic-like effect induced by TRPV1 receptor activation within the dorsal periaqueductal gray matter in mice.

Pharmacological manipulation of TRPV1 (Transient Receptor Potential Vanilloid type-1) receptors has been emerging as a novel target in the investigation of anxiety states. Here, we attempt to show the role played by the TRPV1 receptors within the dorsal periaqueductal gray matter (dPAG), a midbrain structure strongly involved in the modulation of anxiety. Anxiety was assessed by recording spatiotemporal [percent open arm entries (%OE) and percent open arm time (%OT)] and ethological [e.g., head dipping (HD), stretched-attend postures (SAP)] measures in mice exposed to the elevated plus-maze (EPM). Mice received an intra-dPAG injection of the TRPV1 agonist capsaicin (0, 0.01, 0.1 or 1.0nmol/0.2µL; Experiment 1) or antagonist capsazepine (0, 10, 30 or 60nmol/0.2µL; Experiment 2), or combined injections of capsazepine (30nmol) and capsaicin (1.0nmol) (Experiment 3), and were exposed to the EPM to record spatiotemporal and ethological measures. While capsaicin produced an anxiogenic-like effect (it reduced %OE and %OT and frequency of SAP and HD in the open arms), capsazepine did not change any behavior in the EPM. However, when injected before capsaicin (1.0nmol), intra-dPAG capsazepine (30nmol-a dose devoid of intrinsic effects) antagonized completely the anxiogenic-like effect of the TRPV1 agonist. These results suggest that the anxiogenic-like effect produced by capsaicin is primarily due to TRPV1 activation within the dPAG in mice, but that dPAG TRPV1 receptors do not exert a tonic control over defensive behavior in mice exposed to the EPM.